Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
  • C07D213/82—Amides; Imides in position 3
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
  • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/02—Ortho- or ortho- and peri-condensed systems
  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
  • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes

Definitions

• the present invention relates to new derivatives of 2-amino pentanedioic acid, their process and the preparation intermediates, their application as medicament and the compositions containing them.
• R1 represents : - or else an aryl radical containing up to 14 carbon atoms optionally substituted by one or more substituents chosen from the group consisting of halogen atoms, alkyl or alkyloxy radicals containing up to 8 carbon atoms, dialkylamino radicals containing up to 16 carbon atoms and the radicals CF3, cyano or nitro, - or else a heterocyclic radical chosen from the group consisting of the indolyl, pyridyl, piperidinyl, quinolyl and thiazolyl radicals, - or else an arylalkyl radical containing up to 18 carbon atoms optionally substituted on the aryl ring by one or more of the substituents indicated above when R1 represents an aryl radical and either R2 represents : - or a radical in which Ar and Ar ′ identical or different represent an aryl radical containing up to 14 carbon atoms optional
• the compounds of the invention have one or more asymmetric carbons, they can therefore exist in racemic form or in an enantiomeric form, they all have an asymmetric carbon in position 4, and can also have other asymmetric carbons depending on the values of the substituents .
• R1 represents an aryl radical, it is preferably an optionally substituted phenyl radical.
• a halogen atom it is preferably meant the chlorine and bromine atoms.
• R1 represents an aryl radical substituted by an alkyl radical, it is preferably a phenyl radical substituted by a methyl, ethyl, n-propyl or isopropyl radical.
• R1 represents an aryl radical substituted by an alkyloxy radical, it is preferably a phenyl radical substituted by a methoxy, ethoxy or n-propoxy radical.
• R1 represents an aryl radical substituted by a dialkylamino radical, it is preferably a phenyl radical substituted by a dimethylamino or diethylamino radical.
• R1 represents an arylalkyl radical, it is preferably a benzyl radical, a radical -CH2-CH2-C6H5, or (CH2) 3C6H5 optionally substituted by one of the substituents already indicated, or also the cinnamic radical.
• Ar and Ar ′ preferably represent an optionally substituted phenyl radical.
• radicals are preferably radicals: possibly substituted and especially radicals:
• R4 represents an alkyl radical, it is preferably a methyl, ethyl, n-propyl, isopropyl or n-butyl radical.
• R4 represents an arylalkyl radical, it is preferably a benzyl radical, optionally substituted.
• R4 represents a radical: it is preferably the radical:
• R1 represents an indolyl radical
• R2 represents a radical: in which the phenyl rings are optionally substituted by one or more of the substituents listed above for R1, and very especially the compounds in which R2 represents the radical:
• R2 represents a radical: as well as those in which R4 represents a hydrogen atom.
• the subject of the invention is of course very particularly of course the compounds the preparation of which is given below in the experimental part and very especially the compounds of Examples 2, 4, 9 and 13.
• the compounds of formula (I) are agonists or antagonists of cholecystokinin, the binding sites of which have been demonstrated at the central and peripheral levels.
• Cholecystokinin is a peptide widely distributed in the brain, especially in the cortex, striatum, hippocampus, ventral tegmentum, septum and hypothalamus.
• Cholecystokinin is also secreted at the peripheral level by the small intestine, its action is manifested in particular by the stimulation of vesicular contraction, an increase in bile secretion, the control of pancreatic enzyme secretion, an action on gastric contractions, action on intestinal motility. It could act in certain cases on blood pressure and influence the immune systems.
• Cholecystokinin coexists in certain central neurons with dopamine. It is also involved in mechanisms involving acetylcholine, gaba, serotonin, opioids, somatostatin, substance P and ion channels.
• the compounds of formula (I) can therefore be used as medicaments in the treatment of certain eating disorders, of obesity, in behavioral, emotional, sexual and memory disorders, in schizophrenia and in various disorders of the sphere. gastrointestinal.
• the subject of the invention is therefore, as medicaments, the compounds of formula (I), and very particularly the compounds whose preparation is given below in the experimental part, in particular the products of Examples 2, 4, 9 and 13.
• the dosage which varies depending on the product used and the condition in question, can range, for example, from 0.05 mg to 100 mg per day in adults by oral route.
• the present application also relates to pharmaceutical compositions which contain, as active principle, at least one of the abovementioned medicaments. These compositions are produced so that they can be administered by the digestive or parenteral route.
• They can be solid or liquid and come in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, capsules, granules, suppositories, injectable preparations; they are prepared according to the usual methods.
• the active ingredient (s) can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
• excipients usually used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not , fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
• the subject of the invention is also a preparation process, characterized in that a compound of formula (II) is subjected: in which BOC represents the radical (1,1-dimethyl ethoxy) carbonyl and R′4 has the same meaning as R4 with the exception of the hydrogen value, to the action of a compound of formula (III): in which R2 and R3 retain their previous meaning to obtain the compound of formula (IV): which is subjected to the action of an agent for unblocking the amine function, then subject the resulting product to the action of an acid or acid derivative of formula (V): R1CO2H (V) in which R1 retains its previous meaning to obtain the compound of formula (I A ): which is subjected if desired to the action of an agent for cleavage of the acid function to obtain the compound of formula (I B ):
• the compound of formula (III) is used in the form of a salt, for example of hydrochloride
• R′4 represents a benzyl radical
• the agent for unblocking the amine function is a strong acid, for example hydrochloric acid, or trifluoroacetic acid, and one operates within an organic solvent such as methylene chloride or acetate d 'ethyl
• - the acid of formula (V) is used in the form of acid, acid chloride or acid anhydride
• the release agent of the acid function is hydrogen in the presence of palladium or a base such as soda, potash, potassium carbonate, lithium hydroxide, and it is preferably carried out within 'A solvent such as ethanol, dioxane, tetrahydrofuran, methanol, dimethylformamide at a temperature between about 0 ° C and the reflux temperature of the solvent used.
• the subject of the invention is also a variant of the preceding process, characterized in that a compound of formula (VI) is subjected: in which R′4 has the meaning indicated above for the action of an acid or an acid derivative of formula (V): R1CO2H (V) in which R1 has the meaning indicated above for obtaining the compound of formula (VII): which is subjected to the action of a compound of formula (III): in which R2 and R3 have the meaning indicated above to obtain the corresponding compound of formula (I A ) which is subjected if desired, to the action of an acid cleavage agent to obtain the compound of formula ( I B ), (I A ) and (I B ) being defined as above.
• benzyl ester obtained are hydrogenolized previously in the presence of 500 mg of 10% palladium on carbon in a mixture of 50 cm3 of ethanol and 10 cm3 of acetic acid. After absorption of the desired amount of hydrogen, the catalyst is filtered. The solvents are removed under reduced pressure, the residue obtained is taken up in 50 cm3 of ether. A white solid is obtained. Mp 118 ° C.
• the mixture is allowed to return to ambient temperature and kept stirring for 1 night.
• a stream of hydrogen is passed in the presence of 500 mg of palladium on activated carbon at 10% in a solution containing 2.56 g of product obtained in stage B, 250 cm3 of absolute ethanol and 5 cm3 of acetic acid.
• the catalyst is filtered.
• the solvent is removed and the residue obtained is crystallized from ethanol. 2.2 g of the sought product F> 260 ° C. are obtained.
• Tablets corresponding to the following formula were prepared: - Product of Example 2 20 mg - Excipient qs for a tablet finished at 300 mg (Details of excipient: lactose, wheat starch, processed starch, rice starch, magnesium stearate, talc).
• cortices of 20 male rats weighing 150 to 200 g are removed, these cortices are ground with Polytron in 0.32 M sucrose.
• pellets are resuspended in 120 ml buffer HEPES pH 7.4 (Hepes 10 mM, NaCl 130 mM, MgCl2, 6H2O mM, bacitracin 250 mg / l, PMSF 1 mg / l), and recentrifuged.
• the pellets are taken up in 120 ml of Hepes buffer pH 7.4 and centrifuged again at 30,000 g for 30 min.
• the pellets thus obtained are taken up in 500 ml of Hepes buffer pH 7.4, which makes it possible to obtain 240 aliquots of 2 ml of homogenate.
• Incubation is carried out at 25 ° C, 30 min in the presence of 0.5 nM of 3H CCK8 and of the product to be tested (10,000 micromoles for 1 dose, or with a range of 7 doses) or of cold CCK8 (10 ⁇ 6M ), which is the benchmark product.
• pancreas of 3 male rats, 150-200 g are removed and ground with Polytron (4 grindings, speed 3, with an interval of 10 seconds between grindings); the homogenate is filtered through a gauze, then centrifuged at 30,000 g for 30 minutes.
• the pellets obtained are taken up in 400 volumes ( ⁇ 600 ml) of 50 mM Tris buffer HCl pH 7.4, containing BSA 2 g / l, 0.1 mM bacitracin, Mg Cl2 5 mM, 5 mM dithiothreitol.
• the aliquots are filtered through Whatman GF / B filters, prewashed in a 0.05% polyethylene imine solution. Wash with 3 ⁇ 5 ml of 50 mM Tris HCl buffer, pH 7.4.
• the tests are carried out on batches of 5 rats weighing 250 ⁇ 10 g under the following conditions: the animals are placed individually in cages having a manger described by FREGLY (J. Appl. Physiol., 1960, 15 , 539) which exhibits the advantage of avoiding wastage of food consisting of pulverized feed. Rats are used to taking their daily ration in 5 consecutive hours, drinking water being offered ad libitum.
• the amounts of food ingested are determined individually by weighing the feeders. Consumption is monitored hourly for 5 hours after administration of 10 mg / kg i.p. of the compound. The amounts consumed are expressed in g / 100 g of body weight, per hour.
• the means are compared with those obtained in control animals by a DUNNETT test.
• Example 9 shows an anorectic activity.
• Example 2 reduces food consumption by 15%, in a statistically insignificant manner.
• the test is carried out on male guinea pig ileum fragments, placed under a tension of 1 g in a Krebs solution aerated with carbogen and maintained at 37 ° C. Contractions are recorded using a microdynamometer connected to a polygraph.
• the ileum is left to stand for 30 minutes, then the CCK8 is added to the bath at a concentration of 1-10 ⁇ 8M.
• the product to be studied is added to the bath, left in contact for 1 minute with the organ, then CCK8 (1-10 ⁇ 8M) is added to the bath.
• the possible antagonism is expressed by comparing the contractions generated by CCK8 before and after contact with the product to be tested.
• Example 9 The product of Example 9 at a dose of 10 ⁇ 6 M has an interesting antagonistic activity.

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• Chemical & Material Sciences (AREA)
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• Animal Behavior & Ethology (AREA)
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• Neurology (AREA)
• Biomedical Technology (AREA)
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• Indole Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Hydrogenated Pyridines (AREA)
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• 1989
  • 1989-02-17 FR FR8902093A patent/FR2643371B1/fr not_active Expired - Fee Related
• 1990
  • 1990-02-12 US US07/478,479 patent/US5064853A/en not_active Expired - Fee Related
  • 1990-02-15 EP EP90400416A patent/EP0383690A1/de not_active Withdrawn
  • 1990-02-16 JP JP2034048A patent/JPH02264750A/ja active Pending

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